This is a request for a Competitive Revision in response to NIH Notice NOT-OD-09-058. The parent grant is entitled "Genetics of Diabetes in the Amish" (R01 DK04261;Shuldiner, PI). The proposed study builds upon findings from the parent grant and expands the scope of its specific aims, research design, and methods. Specifically, the focus of the parent grant is to apply high throughput genomic approaches in human samples to localize the gene(s) on chromosome 1q21-q24 responsible for linkage to type 2 diabetes (T2D) in the Amish and several other populations. This work identified nitric oxide synthase associated protein 1 (NOS1AP) as a gene likely to be involved in human type 2 diabetes and obesity. The objective of this competitive revision is to extend these findings into a mouse model to explore the functional consequences of Nos1ap deficiency on obesity and metabolism. We hypothesize that Nos1ap knockout (KO) mice will have increased propensity for weight gain, altered insulin secretion, glucose intolerance/diabetes, and hyperlipidemia compared to its wild type littermates. We will generate homozygous Nos1ap KO mice from a previously established Nos1ap KO embryonic stem cell line (Texas A&M Institute of Genomic Medicine). These mice and their wild type littermates will be subjected to normal chow and high fat diets. Metabolic phenotyping, some of which will be performed at the NIDDK-funded Yale Mouse Metabolic Phenotyping Center, will include body composition, food intake, energy expenditure, glucose tolerance, insulin secretion, insulin sensitivity, and lipid homeostasis. If our hypothesis is correct, it would implicate for the first time NOS1AP as an important regulator of glucose and lipid metabolism and energy homeostasis, which may have important implications for the design of new prevention and treatment interventions for T2D and related metabolic complications. As mandated by the American Recovery and Reinvestment Act of 2009, funding of this competitive revision will stimulate the economy by providing job opportunities and security for professional and technical staff and through purchase of supplies, reagents and services at the University of Maryland, and through fee for service arrangements, also at Yale University School of Medicine and Texas A &M University. Furthermore, it will accelerate the pace of diabetes research, which could lead to long-term costs savings associated with improved treatment and prevention of T2D. PUBLIC HEALTH RELEVANCE: Type 2 diabetes and obesity are major U.S. public health problems that inflict enormous morbidity, mortality and health care costs. This work may provide novel mechanistic insights leading to new and more effective strategies for treatment and prevention. In addition, as part of the American Recovery and Reinvestment Act, this Competitive Revision will provide job opportunities and security and stimulate the economy.